1. Field of the Invention
The present invention relates to stilbenoids that exhibit hypotriglyceridemic activity in mammals. Provided herein are processes for obtaining such stilbenoids, particularly from Cajanus cajun; compositions comprising the stilbenoids and methods for their use in dietary supplements for administration to mammals suffering from elevated serum triglyceride levels and for normalizing serum triglyceride levels.
2. Related Art
Uses of Cajanus SPP
Plants of Cajanus spp. (Leguminoseae), particularly C. cajun, also known as pigon pea or redgram, are herbaceous members of the family Leguminoseae that grows widely throughout Africa, Asia and South and Central America. Cajanus spp. have been used in traditional medicine to treat stomach aches for women suspected of being pregnant, to treat wounds and scalds, to treat toothache, against gonorrhoea, to treat bad vison; and against heart diseases (Hedberg, H, et al., J Ethnopharmacol, 9 (2/3), 237-260 (1983).
In addition to its use by traditional healers, these plants may also be included in the normal diet as a food plant. Canjanus spp are consumed by people in India, especially those of the lower economic levels. To that end, studies have reported that rats fed redgram, blackgram and horsegram exhibited a lipid lowering effect.(Saraswathi Devi, K., et al., Atherosclerosis, 11, 479 (1970)).
Extracts from various Leguminosae plants have been reported to exhibit hypotriglyceridemic activity. Jahromi reported a hypolipedemically active ethylacetate fraction extracted from a hypolipedemically active aqueous decoction of Pterocarpus marsupium (Leguminosae). Jahromi, M. A. F, et al., J. Nat. Prods. 56(7), 989-994 (1993). Investigations have also reported an active hypertriglyceridemic agent of redgram contained in an extracted protein (globulin) fraction. Prema, L., et al., Atherosclerosis 18, 369-277 (1973). Prema, L., et al., Indian J. Biochem. Biophys., 10, 293-296 (1973).
While extracts of the genus Cajanus have been used medicinally, such use is not without potential drawbacks. First, in addition to containing one or more compounds having a xe2x80x9cdesiredxe2x80x9d biological activity, plant materials often contain a myriad of naturally-occurring organic compounds among which one or more can elicit a physiological or pharmacological response that contraindicate use for the desired activity. Secondly, when administered in the form of a plant extract, the actual dosage of the unknown active compound(s) is impossible to regulate, which can result in an ineffective amount, i.e., too low or too high a concentration, of active compound administered.
Thus, there remains a need for an isolated or a purified, hypoglycemically, hypotriglyceridemically active compound, compositions comprising effective amounts of such a compound and methods for their use.
Isolated Stilbenoids
The term stilbenoid refers to stilbenes, bibenzyls (7,8-dihydrostilbenes) and phenyldihydroisocoumarins together with a number of nitrogen free phenatlirenols, which are thought to be products of the same metabolic pathway that leads to stilbenes. Gorham, J., The Stilbenoids in Progress in Phytochemistry, Vol. 6, Reinhold, et al., eds., Pergamon Press, New York, 1980, pp 203-252. Stilbenes (7,8-dihydrostilbenes) generally have two stereoisomeric forms, a trans- or a cis-skeleton: 
Generally, naturally occurring stilbenes and bibenzyls are hydroxy and/or methoxy substituted at the 3,3xe2x80x2,4,4xe2x80x2,5, and 5xe2x80x2 positions. Some naturally occurring stilbenes and bibenzyls include pinosylvin (3,5 -dihydroxy stilbene), piceatannol (3,3xe2x80x2,4,5xe2x80x2-tetrahydroxlystilbene), piceid (3,4xe2x80x2,5-trihydroxystilbene-3-O-xcex2-D-glucopyranoside) and resveratrol (3,4xe2x80x25-trihydroxystilbene). Mono-(3 -hydroxy-5-methoxystilbene) and di-methyl (3,5-dimethoxystilbene) ethers of trans-pinosylvin and their respective dihydroderivatives have been reported isolated from the heartwood of Pinus armandi, P. morrisonicola, and P. parviflorai. Fang, J-M, et al., Phytochemistry 27(5): 1395-1397 (1988).
Stilbenoids may also be prenylated or homogeranylated at the 2 and 4 (4 and 6) positions. 4-isopentenylresveratrol (3,4xe2x80x2,5-trihydroxy-4-(3-methyl-2-butenyl)stilbene) was isolated from Arachis hypogea (Keen, N. T., et al., Phytochemistry 15, 1794 (1976)). A prenylated pinosylvin dimethyl ether (3,5-dimethoxy-4-(3-methyl-2-butenyl)stilbene) was isolated from Derris rariflora (Braz Filho, R., et al., Phytochemistry 14, 261 (1975a)) and D. floribunda (Braz Filho, R., et al, Phytochemistry 14, 1454 (1975b)). A prenylated resveratrol trimethyl ether (3,4xe2x80x2,5-trimethoxy-4-(3-methyl-2-butenyl)stilbene) was also reported isolated from D. floribunda (Braz Filho, R., et al., 1975b). Chlorophorin (4-homogeranyl-2,3xe2x80x2,4,5xe2x80x2-tetrahydoxystilbene) was isolated from Chlorophora excelsa (Grundon, M. F., et al., Nature (Lond.) 163, 154 (1949)). The occurrence in plants of isoprenice chains substituted stilbenes has also been reported by King and Grundo (J. Chem. Soc. 1950, 3547 (1950)), Cooksey (Cooksey, C. J., et al., Phytochemistry 21(12), 2935 (1982)) and Monache (Lloydia 40(2): 201-208 (1977)).
Stilbenoid-2-carboxylic acid derivatives have been isolated from various plants. Hydrangeic acid (3,4xe2x80x2-dihydroxystilbene-2-carboxylic acid) was reported isolated from the common garden hydrangea (Hydrangeqa macrophylla) Pryce, R. J., Phytochemistry 10, 2679 (1971). A glycoside, gaylussacin, reported isolated from Gaylussacia frondosa, and G. vassata (Ericaceae), produced a 3,5-dihydroxystilbene-2-carboxylic acid derivative (gaylussacin aglycone). Askari, A., et al., Lloydia 35,49 (1972).
Stilbenoids Isolated from Cajanus spp.
Four isoprenylated stilbene 2-carboxylic acid phytoalexins (3-hydroxy-5-methoxy-6-(3-methyl-2-butenyl) stilbene-2-carboxylic acid, 3-hydroxy-5-methoxy-4-(3-methyl-2-butenyl)stilbene-2-carboxylic acid, 3,5-dimethoxy-6-(3- methyl-2-butenyl)stilbene-2-carboxylic acid, and 3,5-dimethoxy-4-(3-methyl-2-butenyl)stilbene-2-carboxylic acid) were reported isolated from the leaves of Canjanus cajan challenged with Botrytis cinerea (Cooksey, C J, et al., Phytochemistry 21(12):2935-2938 (1982).
Biological Activity of Stilbenoids
Various biological activites have been reported of the stilbenoids. For example, cis-piceid; trans-, cis-resveratrol, astringin and astringinin from Vitis vinifera were tested for antioxidant activities (A. Fauconneau, B., et al., Life Sci. 61(21): 2103 (1997)). 3,3xe2x80x2,4,5xe2x80x2-tetrahydroxystilbene was reported to have strong antifungal activity (Inamori, Y., et al., Chem. Phar. Bull. 33(7):2904-09 (1985)). Resveratrol has also been reported to exhibit antiplatelet aggregation activity. Chung, M-I, et al., Planta Med. 1992 58:274-275; and Kimura, Y., et al., Biochim. Biophys. Acta 1995 175, 275-278); coronary vasodilator activity (Inamori, Y., et al., Chem. Pharm. Bull. 35, 887-89 (1987), anti-leukemia activity (Mannila, E., Phytochemistry, 1003, 33, 813-816), anti-fungal activity (Lanagcake, P., et al., Phytochemistry 1979, 18, 1025-1027; Hart, J. H/., et al. Phytopathology 1979 69:1138-1143) and protein-tyrosine kinase inhibitory activity (Orsini, F., et al., J. Nat. Prods. 60 1082-1087 (1997)).
The antitriglyceridemic activity of stilbenoids has also been investigated. Piceid (3,4xe2x80x2,5-trihydroxystilbene-3-O-xcex2-D-glucopyranoside) isolated from the roots of Polygonum cuspidatium (also known as xe2x80x9cKojo-konxe2x80x9d and xe2x80x9cItadori-konxe2x80x9d) has been reported to lower serum triglyceride and liver lipid levels. Arichi H., et al., Chem. Pharm. Bull. 30(5) 1766-1770 (1982). 2,3,5,4xe2x80x2-tetrahydroxy stilbene-2-O-D-glucoside isolated from Polygonum multiflorum has also been reported to reduce serum triglyceride levels. Arichi, H, et al., 1982.
Inventors are not aware, of any prenylated or 2-carboxylic acid stilbenoids reported to exhibit antihypertriglyceridemic activity. Inventors are not aware, however, of any stilbenoids isolated from Cajanus spp reported to exhibit antihypertriglyceridemic activity.
Citation or identification of any reference described herein shall not be construed as an admission that such reference is available as prior art to the present invention.
The present invention provides compositions comprising a hypotriglyceridemically effective amount of an isolated compound of the formula: 
wherein
A is a bond selected from the group consisting of a single bond and a double bond in trans conformation, as noted by - - - ;
R1 and R3 are independently selected from the group consisting of H, OH, and C1-6alkoxy;
R2 and R4 are independently selected from the group consisting of H, C1-10alkyl, C2-10alkenyl, and C2-10alkynyl;
R5 and R6 are independently selected from the group consisting of H, OH, and C1-6alkoxy;
or pharmaceutically acceptable salts thereof.
The present invention also provides methods to reduce blood triglyceride levels in a mammal comprising administration of a composition of the present invention. The compositions of the present invention are useful to treat hypertriglyceridemia in mammals.